Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality in the United States and throughout the developed world. CVDs share a common pathophysiology - atherosclerosis. Atherosclerosis is a chronic inflammatory disease influenced by circulating cells, including platelets. Platelets play a central role not only in the process of thrombus formation, but also in atherogenesis and the progression of atherosclerotic lesions. Platelet hyperactivity is likely an important factor in the progression of subclinical cardiovascular disease (CVD) in healthy adults. Obesity and dietary sodium are two factors that have been linked to both CVD and altered platelet function. Obese individuals have an increased risk of thrombosis, which may be partially explained by platelet hyperactivity. It has also been suggested that obese individuals are more salt-sensitive than normal weight individuals, which may place them at an increased risk for negative cardiovascular changes associated with a high salt diet. It is proposed that lifestyle changes, such as weight loss and reduced dietary sodium, reduce platelet hyperactivity in obese individuals. The proposed project aims to assess in vivo platelet hyperactivity in overweight and obese participants in a lifestyle intervention trial evaluating the effects of weight loss, increased physical activity, and sodium restriction on vascular remodeling (R01 HL077525-04). Although both obesity and high dietary sodium have been linked to in vitro platelet hyperactivity, these factors'and other CVD risk factors'associations with in vivo platelet activation remain unclear, as does the extent to which genetics influences in vivo platelet activation in healthy individuals. The proposed project will measure in vivo platelet activation as plasma 2-thromboglobulin (2-TG) using an enzyme immunoassay. 2-TG is released specifically by platelets only upon their activation. Plasma markers of in vivo platelet activity, such as 2-TG, are easily measured and accurately reflect basal levels of platelet activity. The proposed project will identify whether in vivo platelet hyperactivity (high 2-TG) is associated with dietary sodium, CVD risk factors, measures of vascular adaptation, and whether several functional polymorphisms in platelet receptor genes influence in vivo activation and vascular adaptation. The specific aims of this project are to determine, in an overweight/obese population, (1) whether in vivo platelet hyperactivity is positively associated with dietary sodium intake (2) which CVD risk factors are associated with platelet hyperactivity (3) if in vivo platelet hyperactivity is positively associated with measures of subclinical CVD or their rates of change and (4) whether functional variants in platelet receptor genes influence in vivo platelet activation and subclinical CVD measures. By shedding light on the determinants of platelet hyperactivity and its role in vascular remodeling, this project will improve our ability to target currently healthy overweight and obese adults for appropriate lifestyle changes for primary CVD prevention, thereby contributing to reducing the burden of CVD experienced by overweight and obese individuals. PUBLIC HEALTH RELEVANCE: This project will identify genetic, physiologic, and lifestyle factors associated with elevated platelet activity and vascular remodeling in healthy overweight and obese adults. In particular, lifestyle changes such as weight loss and dietary sodium reduction will be evaluated for their abilities to reduce the platelet hyperactivity found in obese individuals. Because platelets are a key culprit in cardiovascular disease, this project will contribute to our understanding of how to reduce the excess cardiovascular disease risk experienced by overweight and obese individuals.